The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis

Aim To evaluate the effect of diabetes mellitus type 2 (T2DM) on the outcomes after treatment of hepatocellular carcinoma (HCC). Methods PubMed and Cochrane Central Register of Controlled Trials Databases were systematically searched. Three HCC clinical outcomes were explored: death, progressive disease after locoregional therapies, and recurrence. Sub-analysis was performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between T2DM and non-T2DM groups. Results A total of 27 studies were analyzed. Overall, 85.2% of articles were from Asia. T2MD was associated with an increased risk of death (OR 3.60; 95%CI 2.18-5.95; P < 0.001), irrespective of the treatment approach: curative (OR 1.30 95%CI 1.09-1.54; P = 0.003) or non-curative (OR 1.05; 95%CI 1.00-1.10; P = 0.045), increased HCC recurrence (OR 1.30; 95%CI 1.03-1.63; P = 0.03), and increased disease progressiveness (OR 1.24; 95%CI 1.09-1.41; P = 0.001). Conclusions Current data provide strong evidence that T2DM unfavorably affects HCC progression and recurrence, and patients' survival after treatment, irrespective of the approach used.

The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is increasing (1,2) as the result of the globally increased prevalence of NALFD, which is estimated to be about 25% (3). NAFLD patients have a two-to three-fold increase in the risk of developing diabetes mellitus type 2 (T2DM), and the risk is even higher in those with more severe hepatic disease and fibrosis (4)(5)(6). On the other hand, patients with T2DM have a higher prevalence of non-alcoholic steatohepatitis (NASH), liver fibrosis, and end-stage liver disease (7).
Several studies have documented the relation between T2DM and the incidence of different cancer types, while the data on the relationship between T2DM and increased risk of incident HCC seem especially robust and clinically reliable (8)(9)(10). Observational studies suggest higher mortality of patients developing HCC in the presence of T2DM (11,12). On the other hand, data from meta-analyses suggest that both the risk and prognosis of patients with HCC and diabetes might be influenced by the type of anti-diabetic treatment, where metformin, unlike sulphonylurea, potentially protects against cancer and leads to better prognosis in case of cancer development (13,14).
The underlying mechanisms linking T2DM and HCC are still under scientific scrutiny. However, the interconnections between metabolic derangements characteristic for T2DM, obesity, and NAFLD suggest that insulin resistance on the hepatic and systemic level and the release of pro-inflammatory cytokines, vasoactive factors, and pro-oxidant molecules are potentially implicated in the development and progression of HCC.
With the intent to gain a better insight into this issue, we performed a meta-analysis to evaluate the effect of T2DM on poor outcomes after HCC treatment. To explore several different clinical settings, three outcomes of interest were investigated: death, progressive disease after locoregional therapies, and recurrence. Moreover, sub-analyses were performed according to the use of potentially curative (resection, transplantation, termo-ablation) or noncurative therapies.

Search sources and study design
A systematic review of the published literature was undertaken focusing on the role of T2DM in the outcomes of HCC patients receiving any tumor therapy. The search strategy followed the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) guidelines (15). In terms of inclusion criteria, data extraction, quality assessment, and statistical analysis, we used the same methodological approach as in our previous article (16).
The research question formulated in the present study included the following Patients, Intervention, Comparator, Outcome components: Patient: patients with HCC and T2DM; Intervention: any HCC therapy; Comparison: patients with HCC without T2DM treated with the same approach; Outcome: death, progressive disease, or recurrence.
We searched the PubMed and Cochrane Central Register of Controlled Trials databases using the following terms: (recurrence or death or survival) and (diabetes or T2DM) and (HCC or hepatocellular cancer or hepatocellular carcinoma or hepatoma). The search period was from 2000/01/01 to 2020/11/30. The systematic qualitative review included only studies in English that involved human patients. Reports were excluded based on several criteria: a) data on animal models; b) studies that lacked enough clinical details; c) studies that had non-primary source data (eg, review articles, non-clinical studies, letters to the editor, expert opinions, and conference summaries). In the case of studies originating from the same center, the possible overlapping of clinical cases was examined, and the most informative study was considered eligible.

Data extraction and definitions
After a full-text review of the eligible studies, two independent authors (QL and FG) extracted the data and crosschecked all outcomes. During article selection and data extraction, potential discrepancies were resolved by a consensus with a third reviewer (AM). Collected data included the first author of the publication, year of publication, country, and the number of treated and recurred patients according to the different therapies adopted.

Quality assessment
Selected studies were systematically reviewed with the intent to identify potential sources of bias. The ar-ticles' quality was assessed by using the Risk of Bias In Nonrandomized Studies of Interventions (ROBINS-I) tool (17).

Statistical analysis
The results are expressed as odds ratio (OR) with 95% confidence intervals (CIs). The statistical heterogeneity was evaluated with the Higgins statistic squared (I2). I2 values of 0%-25% were considered as an index of low heterogeneity between studies, 26%-50%: moderate heterogeneity, and ≥51%: high heterogeneity. The fixed-effects model was used when low or moderate (0%-50%) heterogeneity was detected between studies, while the random effects model was used when high heterogeneity was present. The value P < 0.05 indicated statistical significance. The meta-analysis was performed by using OpenMetaAnalyst (http://www.cebm.brown.edu/openmeta/index.html).

Qualitative assessment of the included studies
All the 27 selected articles were retrospective analyses. As for the ROBINS-I tool quality assessment, all the studies had a low risk of bias.

Death in HCC patients with vs without T2DM
Twenty-three studies reported post-treatment death rates in HCC patients with vs without T2DM (Table 1). Two studies contextually reported both data on post-hepatic resection and post-non-curative approach cases (21,37).

Recurrence in HCC patients with vs without T2DM
Fourteen studies reported post-treatment recurrence rates in HCC patients with vs without T2DM (Table 2). A total of 40 021 patients were considered, with 13 469 (33.7%) recurrences. In detail, 3609/10 641 (33.9%) and 9860/29 462 (33.5%) recurrences were observed in the T2DM and no-T2DM group, respectively. The selected studies showed great heterogeneity, with an I2 = 79.1% (P < 0.001). Most of the studies showed a lower risk of recurrence in T2DM absence ( Figure 4). The summary OR showed an increased risk of recurrence in T2DM patients, being 1.30 (95%CI 1.03-1.63; P = 0.03). Progressive disease in HCC patients with vs without T2DM Seven studies reported post-treatment progressive disease rates in HCC patients with vs without T2DM (Table 3)

Death in HCC patients with vs without T2DM after curative or non-curative treatments
Thirteen studies reported death rates in HCC patients with vs without T2DM after a curative treatment, namely radiof-requency ablation, hepatic resection, and transplantation ( Most of the studies showed a lower risk of death in T2DM absence ( Figure 6A). The summary OR showed an increased risk of death in T2DM patients after curative approach, being 1.30 (95%CI 1.09-1.54; P = 0.003).
Six studies reported death rates in HCC patients with vs without T2DM after a non-curative treatment, namely any therapy other than radiofrequency ablation, hepatic resection, and transplantation.   with an I2 = 13% (P = 0.33). Most of the studies showed a lower risk of death in T2DM absence ( Figure 6B). The summary OR showed an increased risk of death in T2DM patients after non-curative approach, being 1.05 (95%CI 1.00-1.10; P = 0.045).

DISCUSSION
Our study found strong evidence that T2DM unfavorably affects HCC patients' outcomes in terms of progression and recurrence of the disease and patients' survival after treatment, irrespective of the approach used.
HCC is a common malignancy with still unfavorable prognosis (45). Among the growing risk factors for its development are metabolic derangements associated with NASH and T2DM, with insulin resistance as a common denominator (46). In addition, NAFLD-related HCC occurs both in tandem and in the absence of underlying cirrhosis, substantiating NAFLD's tumorigenic effects (47,48). Accord-  ing to epidemiologic studies, T2DM can increase the incidence of HCC and unfavorably alter the prognosis of patients with HCC (49).
In reference to its multisystemic effects, T2DM, in some centers, is considered a relative or absolute contraindication for curative treatments such as liver transplantation  due to poor outcomes and higher incidence of complications (50). Nevertheless, a recent meta-analysis showed that NAFLD-HCC patients could enjoy long-term survival benefits when treated with aggressive curative approaches (resection, transplantation, or thermo-ablation) with no difference in overall survival compared with non-NAFLD HCC patients (51). On the other hand, this metaanalysis provided solid evidence that T2DM patients compared with non-T2DM patients have an increased risk of death after curative HCC treatments, irrespective of the approach. Most out of 13 studies included in this metaanalysis showed a lower risk of death in T2DM absence. Furthermore, we demonstrated that the same T2DM impact on survival could also be expected after non-curative HCC approaches.
Most studies (85.2%) included in this meta-analysis were from Asia, where hepatitis B infection is still the leading cause of HCC. The incidence of alcohol-and HCV-related HCC in Asian countries is relatively stable and low, while NASH has become a growing epidemic with the prevalence of approximately 10%-20% (52,53). NASH is mainly accompanied by T2DM, dyslipidemia, and obesity, common factors leading to cardiovascular events. NASH is the fastest-growing cause of HCC in US liver transplant candidates (54), and the same is expected to occur in Asia due to changes in eating habits and sedentary lifestyles. NASH is strongly associated with HCC and liver-related mortality, yet the death in NAFLD is due mainly to cardiovascular diseases (55,56).
In addition, this meta-analysis shows that diabetes is inevitably associated with a greater risk of HCC progression. Only a study by Di Costanzo et al (38) showed longer timeto-progression (10 months vs 9 months) in 80 diabetic HCC patients treated with sorafenib compared with 233 non-diabetic HCC patients (38). Other six studies reporting data on HCC progression (17,25,36,40,41,43) showed an increased diabetes-associated risk (26 358 patients with vs 82 893 without diabetes) on HCC progression.
In light of the observed results, it would be prudent to improve the prevention of T2DM by promoting a healthy diet and incorporating structured physical activity into everyday life (57). Moreover, an important role in the prevention of HCC can be played by interventions that lead to T2DM remission, such as those with glucagon-like peptide-1 receptor agonists (liraglutide and semaglutide) and bariatric surgery, which significantly reduce (>10%) and help maintain weight (58)(59)(60)(61). The potential chemo-preventive effect of antidiabetic drugs such as metformin in HCC patients requires further clarification (62).
The present study has some limitations. First, a large part of the investigated population is from Asian countries. Therefore, the reported results should present some geographical peculiarities precluding their generalizability in Western populations. Further larger studies coming from North America and Europe are required. Another limitation relates to the great heterogeneity reported among different studies. Unfortunately, different aims and different approaches were reported in the examined studies, increasing the difficulty to obtain definitive results. We tried to minimize the heterogeneous effect by performing subanalyses focused on specific classes of patients (ie, treated with curative vs non-curative therapies).
Further studies are required to better clarify the effect of T2DM in larger Western series and investigate the effect of anti-diabetic drugs in protecting against the risk of tumor evolution in HCC patients receiving curative or non-curative therapies.
Funding None.
Ethical approval Not required.
Declaration of authorship AM, MCB, and QL conceived and designed the study; FG and QL acquired the data; FG and QL analyzed and interpreted the data; AM and MCB drafted the manuscript; all authors critically revised the manuscript for important intellectual content; all authors gave approval of the version to be submitted; all authors agree to be accountable for all aspects of the work.

Competing interests All authors have completed the Unified Competing
Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.